title: Effect of thrombomodulin on the development of monocrotaline-induced pulmonary hypertension.
abstract: OBJECTIVE
  The purpose of the present study was to investigate whether thrombomodulin (TM) prevents the development of pulmonary hypertension (PH) in monocrotaline (MCT)-injected rats.
  
  
  METHODS
  Human recombinant TM (3 mg/kg/2 days) or saline were given to MCT-injected male Sprague-Dawley rats for 19 (n = 14) or 29 (n = 11) days. Control rats (n = 6) were run for 19 days. The mean pulmonary artery pressure (mPAP), right ventricular hypertrophy (RVH), percentages of muscularized peripheral arteries (%muscularization), and medial wall thickness of small muscular arteries (%MWT) were measured. To determine inflammatory and coagulation responses, broncho-alveolar lavage fluid (BALF) was analyzed in another set of rats (n = 29). Western blotting for endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (peNOS) in the lung tissue was performed in separate rats (n = 13). Survival was determined in 60 rats.
  
  
  RESULTS
  MCT increased mPAP, RVH, %muscularization, and %MWT. TM treatment significantly reduced mPAP, %muscularization, and %MWT in peripheral arteries with an external diameter of 50-100 μm in 19 days after MCT injection, but the effect was lost after 29 days. MCT increased the levels of tumor necrosis factor alpha, monocyte chemoattractant protein-1, and thrombin-antithrombin complex in BALF. Expression of eNOS increased in MCT rats, while peNOS decreased. The relative amount of peNOS to total eNOS increased in MCT/TM rats compared to MCT/Vehicle rats. A Kaplan-Meier survival curve showed no difference with and without TM.
  
  
  CONCLUSIONS
  Although the administration of TM might slightly delay the progression of MCT-induced PH, the physiological significance for treatment is limited, since the survival rate was not improved.
authors.affiliation: Anesthesiology and Critical Care Medicine, Mie University School of Medicine, Mie, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Yamada
authors.forename: Junko
authors.initials: J
authors.lastname: Maruyama
authors.forename: Erquan
authors.initials: E
authors.lastname: Zhang
authors.forename: Amphone
authors.initials: A
authors.lastname: Okada
authors.forename: Ayumu
authors.initials: A
authors.lastname: Yokochi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sawada
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Mitani
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hayashi
authors.forename: Koji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Maruyama
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000378:metabolism; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000503:physiopathology; D053208:Kaplan-Meier Estimate; D008168:Lung / Q000187:drug effects; D008297:Male; D016686:Monocrotaline / Q000633:toxicity*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018180:Thrombomodulin / Q000008:administration & dosage*
chemical_list: D018932:Chemokine CCL2; C546931:THBD protein, human; D018180:Thrombomodulin; C046193:antithrombin III-protease complex; D016686:Monocrotaline; D000990:Antithrombin III; D052250:Nitric Oxide Synthase Type III; D010447:Peptide Hydrolases